Peptide inhibitors of deoxyhemoglobin S gelation have been tested using equilibrium solubility and kinetic assays of sickle hemoglobin gelation. Dipeptides which inhibit gelation do so primarily by the contribution of hydrophobic residues with L-Trp greater than L-TYR greater than L-Phe greater than L-Leu greater than L-Ile greater than L-Val. Other peptides have been designed using computer graphics to study the intermolecular contacts present in the crystal structure. Tripeptides which mimic residues in the side-to-side contact have been synthesized and tested and are capable of inhibiting deoxyhemoglobin S gelation. The mechanism of action of these peptides, i.e., whether they are acting as stereospecific competitive inhibitors of sickle hemoglobin polymerization, is being studied by the X-ray difference Fourier method and spectroscopic methods to facilitate the design of better inhibitors.